Topical anti-inflammatory compositions



United States Patent 2,890,152 TOPICAL AN'II-INFLAMlVIATORY COMPOSITIONS No Drawing. Application November 29, 1956 Serial, No. 624,961

7 Claims. (Cl. 167-65) This invention relates to therapeutic compositions and more particularly to compositions which are useful in the treatment of various dermatogical conditions.

We have found that topical preparations comprising a combination of diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethylpiperidinium methyl sulfate) with hydrocortisone or prednisolone 1,4-pregnadiene-l 15,1711, 21-triol-3,20-dione) offer a long-awaited adjunct in the treatment of a variety of skin diseases. Our new compositions are useful in treating conditions such as dyshidrotic eczematous lesions caused by drug allergies. In place of the free sterol there may be used, in some cases, an ester such as a 2l-acetate or soluble stable ester of phosphoric acid and the like. The composition is especially applicable in the treatment of the disease generally known as intertrigo which is aggravated by sweating and friction between opposing skin surfaces. 'Lesions which occur in the armpit due from sensitivity to a deodorant, for example, and the common diaper ras quickly disappear following local application of our therapeutic combination. Furthermore, many dermatological conditions such as lichen planus, those arising from food ordrug allergies, athletes foot, intertrigo, and the like, are accompanied by severe pruritis, or itching, with weeping of the lesion. The new compositions of this invention have-demonstrated remarkable ability in overcoming pruritic and Weeping manifestations. By so removing the desire to scratch and further aggravate the sores, the topical preparations hasten the cure ofthe disease.

The new therapeutic combinations, described in more detail below, are thus highly effective agents in combatting a host of skin diseases. It is indeed surprising that the particular combination of diphemanil methylsulfate with hy rocortisone orprednisolone enables control of conditions whichare resistant to the action of either active ingredient when used alone.-

' The mode of action ofthecomposition is unknown although absorption of the medicament at the site apparently occurs whereby the development of tissue reaction is counteracted. No toxic reactions arising from the composition have been observed.

There appears to be a potentiation of each of the active ingredients upon each other. Although large doses of hydrocortisone have been used internally or topically to combat certain skin diseases, the presence of diphemanil methylsulfate permits the use of a smaller dose of the corticoid.

Our new compositions consist essentially of the active ingredients suspended or dissolved in a carrier suitable for topical application such as a hydrocarbon base of the petrolatum type, absorption bases, hydrophilic petrolatum bases, water-soluble bases containing polyethylene glycols and lotions. In certain instances a water-soluble base is preferred so as to permit proper healing of weeping lesions and overcome inteltrigo. Diphemanil methylsulfate is particularly adaptable to incorporation into water-soluble bases and water containing bases by virtue iCQ 2 of its stability. It is indeed surprising that of the large number of anticholinergic agents of the quaternary amine type which are in common use in medical therapy, only one, diphemanil methylsulfate, is stable under hydrous conditions. This distinct property is not easily explained but may be due to the chemical structure of diphemanil methylsulfate. The substance is a piperidylidene derivative while for the most part all other anticholinergics are structurally related to atropine and/or contain a dialkaminoalkyl grouping. Laboratory testing of other anticholinergic agents such as methantheline bromide, methscopolamine bromide, propantheline bromide, tricyclarnol methylsulfate, and the like, have demonstrated their incompatibility with hydrous media. Thus our compositions are inherently unique in their content.

The active ingredients of our novel compositions can be incorporated into any suitable ointment or cream base to provide the topical preparations of the present invention. Representative examples of suitable bases are given in the specific examples hereinafter set forth. The nature and composition of such bases are well-known and well understood by those skilled in the preparation and employment of topical medications. While each of the active ingredients present in the compositions of the present invention is ordinarily employed in proportions of from about 0.1 percent to 2.5 percent by weight of the final composition, proportions outside this range can also be used, such as 0.1 to 4 percent diphemanil methylsulfate and 0:1 to 4 percent steroid. For achievement of optimum results, it has been determined that the preferred proportions of the active ingredients present in the composition should be one percent of the cortical hormone and two percent of anticholinergic agent.

The compositions of the present invention can be readily prepared by conventional procedures used in the preparation of topical ointments or creams. For example, the active ingredients can be incorporated into any suitable ointment of cream base by simply admixing in a suitable agitating device, such as a mixer or blender.

The novel topical medications of the persent invention are illustrated by the following examples which are presented for illustrative purposes only.

EXAMPLE 1 Water soluble cream Parts Prednisolone 5.0 Diphemanil methylsulfate 20.0 Zinc stearate 60.0 Polyethylene Glycol i500 405.0 Polyethylene Glycol 6000 120.0 Propylene glycol 350.0 Distilled H O 40.0

EXAMPLE 2 Water soluble ointment Parts Diphemanil methylsulfate 20.0 Hydrocortisone 10.0 Zinc stearate 200.0

CarbOWaX 1500 549.0 Distilled Water 221.0

EXAMPLE 3 Water-removable or hydrophilic preparation Hydrocortisone Parts Hydrocortisone 10.00 Diphemanil methylsulfate 40.00 Methyl Paraben 0.25 Propyl Paraben 0.15 Steryl alcohol 245.00 White petrolatum 245.00 Propylene glycol 120.00 Polyoxyethylene lauryl alcohol 50.00 Distilled Water 290.00 1000.00

EXAMPLE 4 Hydrocarbon ointment Parts Prednisolone 10 Diphemanil methylsulfate 25 Petrolatum U.S.P. 965 1000 A slurry of the prednisolone and diphemanil methylsulfate in about 100 parts of petrolatum is milled. The remainder of the petrolatum is then added and the batch is mixed in an ointment mixture until uniform.

EXAMPLE 5 Absorption formulation Parts Cholesterol 30 Stearyl alcohol 30 White Wax 80 White petrolatum 830 Diphemanil methylsulfate 20 Hydrocortisone Cholesterol is added to a warm melt of the stearyl alcohol, Wax, and petrolatum. The mixture is stirred until the cholesterol completely dissolves. Hydrocortisome is then mixed in by stirring. Diphemanil methylsulfate is added and the mixture is thoroughly stirred and cooled until it congeals.

4 EXAMPLE 6 Lotion preparation Parts Diphemanil methylsulfate 30 Prednisolone 5 Methyl Paraben 0.25 Propyl Paraben 0.15 Stearyl alcohol 245 Propylene glycol 50 Polyoxyethylene lauryl alcohol 10 Distilled water, q.s. to a total of 1000 parts.

This formulation is prepared in the same manner as the hydrophilic preparation of Example 3 except that the petrolatum is omitted.

Having disclosed our invention, what we claim to be new and wish to secure by Letters Patent is:

1. A therapeutic composition of matter comprising a steroid of the group consisting of hydrocortisone and prednisolone in combination with diphemanil methylsulfate and a carrier.

2. A therapeutic composition of matter comprising from about 0.1 percent to about 4.0 percent of a steroid defined in claim 1, from about 0.1 percent to about 4.0 percent diphemanil methylsulfate, the remainder of the composition comprising a viscous supporting carrier.

3. A therapeutic composition of matter comprising from about 0.1 percent to about 2.5 percent of a steroid defined in claim 1, from about 0.1 percent to about 2.5 percent of diphemanil methylsulfate, the remainder of the composition comprising a viscous supporting carrier.

4. A therapeutic composition of matter according to claim 2 in which the steroid is hydrocortisone.

5. A therapeutic composition of matter according to claim 2 in which the steroid is prednisolone.

6. A therapeutic composition of matter comprising essentially the following:

Percent by weight 0.1 to 2.5 0.1 to 2.5

Prednisolone Diphemanil methylsulfate in an aqueous glycol vehicle.

7. A therapeutic composltion of matter comprising essentially the following:

Percent by weight Hydrocortisone 0.1 to 2.5 Diphemanil methylsulfate 0.1 to 2.5

in an aqueous glycol vehicle.

References Cited in the file of this patent 

1. A THERAPEUTIC COMPOSITION OF MATTER COMPRISING A STEROID OXF THE GROUP CONSISTING OF HYDROCORTISONE AND PREDNISOLONE IN COMBINATION WITH DIPHEMANIL METHYLSULFATE AND A CARRIER. 